Endometrial Receptivity Markers In Patients With Ovulatory Polycystic Ovary Syndrome, Endometrioma And Unexplained Subfertility: A Prospective Comparative Study

Research Article | DOI: https://doi.org/10.31579/2578-8965/025

Endometrial Receptivity Markers In Patients With Ovulatory Polycystic Ovary Syndrome, Endometrioma And Unexplained Subfertility: A Prospective Comparative Study

  • Emine Demirel 1*
  • Fulya Oguz 1
  • Melike Demir Caltekin 1
  • Mustafa Sengul 1
  • Burak Yucel 12
  • Sefa Kelekci 1

M.D., Izmir Katip Celebi University Faculty of Medicine, Department of Obstetrics and Gynecology, Izmir, Turkey.

*Corresponding Author: Emine Demirel, M.D., Izmir Katip Celebi University Faculty of Medicine, Department of Obstetrics and Gynecology, Izmir, Turkey.

Citation: Emine Demirel, Fulya Oguz, Melike Demir Caltekin, Mustafa Sengul, Burak Yucel and Sefa Kelekci. (2019) Endometrial receptivity markers in patients with ovulatory polycystic ovary syndrome, endometrioma and unexplained subfertility: A prospective comparative study. Obstetrics Gynecology and Reproductive Sciences, 3(2): DOI: 10.31579/2578-8965/025

Copyright: © 2019. Emine Demirel. This is an open-access article distributed under the termsof the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Received: 27 October 2019 | Accepted: 01 November 2019 | Published: 08 November 2019

Keywords: Endometrıal receptivity; insulin-like growth factor binding protein 1; osteopontin; prostaglandin E2;polycystic ovary syndrome; unexplained subfertility

Abstract

Many molecular markers have been identified in different stages of the luteal phase those play roles in the implantation. Our aim was to compare the levels of insulin-like growth factor binding protein 1 (IGFBP-1), Osteopontin (OPN) and prostaglandin E2 (PGE2) in endometrial washing liquid between women with ovulatory polycystic ovary syndrome (PCOS), endometrioma and unexplained subfertility, compared with ovulatory women. The study groups were formed by women with ovulatory PCOS (n=24), endometrioma (n=17) and unexplained subfertility (n=25). The control group consisted of fertile women (n=18). There were no significant differences in terms of the values of IGFBP1, PGE2 and OPN among groups. There was a statistically significant difference between ovulatory PCOS group and control group in terms of PGE2 levels (p=0.002). High PGE2 might be a marker for poor endometrial receptivity. We supposed that the down-regulation of PGE2 may facilitate decidualization and improve pregnancy rate in ovulatory PCOS.

Impact Statement

  • What is already known on this subject: Endometrial receptivity markers are expressed in the implantation window for successful embryo implantation. Insulin-like growth factor binding protein 1 (IGFBP-1), prostaglandin E2 (PGE2) and osteopontin (OPN) have significant roles in endometrial function and implantation. These would be potential biomarkers of endometrial receptivity.
  • What The Results Of This Study Add: High PGE2 levels in women with ovulatory polycystic ovary syndrome (PCOS) may contribute to endometrial dysfunction and subfertility according to results of our study.
  • What Are The Implications Of These Findings Clinical Practice And/Or Further Research: PGE2 may be an indicator of reduced endometrial receptivity that might be responsible for the low pregnancy rates in women with ovulatory PCOS

Introduction

A successful embryo implantation requires a receptive endometrium, a live embryo and harmonious signalization between them. After the contact between cytokines, growth factors, receptors and blastocyst, junctional complexes are formed. Then blastocyst adhesion and invasion starts via adhesion molecules such as integrins and selectins [1].

The implantation window is defined as that period when the uterus is receptive for implantation of the free-lying blastocyst. Some important growth changes occur during implantation window. Recently, many molecular markers have been identified in different stages of the luteal phase those play roles in the implantation. These endometrial receptivity markers are expressed in the implantation window for successful implantation [2-5]. 

Insulin-like growth factor binding protein 1 (IGFBP-1) has an important role in growth, development and apoptosis in endometrium. It is secreted from the ovarian stroma depending on the phase of the menstrual cycle and has a role in the decidual differentiation of stroma as a specific decidualization marker [6]. Recent studies have shown that androgen precursor dehydroepiandrosterone (DHEA) and the distal upstream region of insulin-like growth factor-binding protein-1 can enhances expression of IGFBP-1 in endometrial stromal cells during decidualization and may improve pregnancy rates in natural or assisted reproductive cycles [7,8]. Osteopontin (OPN) presents in the endometrium in a coordinated manner throughout the menstrual cycle of fertile women and is expressed at maximum levels during the implantation window [9,10].  It was suggested that this protein has complementary roles in endometrial function and implantation and that OPN and its receptor, αvβ3 integrin, complex might be formed to support embryo attachment [10-14]. Furthermore, Wang et al [15] demonstrated that level of OPN is significantly repressed in the failed group when compared with successful pregnancy group in in vitro fertilization (IVF) cycles and therefore evidence supporting the fact that OPN is involved in decidualization and pregnancy success. Prostaglandins are a group of bioactive lipid products formed as a result of arachidonic acid metabolism. Vilella et al [16] suggest that prostaglandin E2 (PGE2) concentrations 24 hours prior to embryo transfer are potential noninvasive biomarkers of endometrial receptivity.

The aim of this prospective cross-sectional study was to compare the levels of IGFBP-1, osteopontin and PGE2 in the late luteal phase endometrial washing fluids of healthy, fertile women and patients with ovulatory PCOS, endometrioma and unexplained subfertility.

Materials and Methods

This study was conducted between January 2013 and June 2013 in subfertility unit of the Department of Obstetrics and Gynecology, School of Medicine, Izmir Katip Celebi University, Izmir, Turkey. The unit is a tertiary center in the west of Turkey that treats referral patients from the region. The study design was in accordance with the ethical standards of the Helsinki declaration and was approved by the Institutional Review Board of İzmir Katip Celebi University School of Medicine (17.05.2012/22). Written informed consent was taken from all volunteers.

One hundred and twelve women between 20 and 40 years’ old were included. Patients were recruited who admitted to subfertility outpatient clinic with a sequential manner because of seeking fertility. Control group was selected among age matched woman who admitted to family planning unit for requesting contraception. Inclusion criteria of study group were ovulatory PCOS, subfertil woman with endometrioma and unexplained subfertility. The control group consisted of fertile women with no gynecologic disorder, not using an intrauterine device or hormonal contraception. Exclusion criteria were anovulatuar woman with PCOS and control group, smoking, pelvic infection, endometrial pathology (endometrial polyp, submucosal myoma etc.) during the endometrial fluid sampling.

Main outcome measure was compare IGFBP-1, PGE2, OPN levels during implantation window in ovulatory PCOS, endometrioma, unexplained subfertility and fertile ovulatory women.

The endometrial fluid sampling was performed after ovulation was confirmed. 0.154 mol/L sodium chloride was administered via a thin cannula. A total of 10 mL (2 mL per administration for 5 times) endometrial fluid sample was collected for each patient. The 1 ml of the aspirate was poured into a standard 1.5 ml micro test tube (Eppendorf, Hamburg, Germany), was frozen at -20°C and was stored in a deep freezer at -80°C until biochemical analyses were performed. After the endometrial fluid samples were collected from the patients, IGFBP-1, osteopontin and PGE2 levels were studied by using East biopharm branded (Hangzhou East biopharm Co., Ltd./China) Elisa kits (PGE2 lot: 20130924, OPN lot: 20130924, IGFBP-1 lot: 20130924, PGE2 Cat. No: CK-E10702, OPN Cat. No: CK-E10857, IGFBP-1 Cat. No: CK-E10159) with the Biotec branded Elisa device.

For the statistical analysis, the SPSS (version15.0, 2006; SPSS Inc., Chicago, IL, USA) program was used. The distribution of the data was controlled by Shapiro-Wilks and Levene’s tests. As the fundamental hypothesis of parametric statistics was not met, instead of parametric MANOVA, use of non-parametric tests was considered appropriate. Hence, for both variables Kruskal-Wallis tests were performed, four groups were tested in the same hypothesis and paired comparisons were made between the groups via Mann-Whitney U tests as follow-up tests in case statistically significant differences were achieved. P<0.05 was accepted as statistically significant.

Results

A total of 120 women were included. The study groups were formed by patients with ovulatory PCOS (n=38), endometrioma (n=19) and unexplained subfertility (n=27). The control group consisted of fertile women (n=28) with no gynecologic disorder, not using an intrauterine device or hormonal contraception. Twenty-eight women (23.3%) with anovulation (a serum progesterone level of <3 ng/dL on the 21st day of menstruation) in both study and control groups were excluded. Twenty-four patients with ovulatory PCOS, 25 with unexplained subfertility, 17 with endometrioma and 18 healthy fertile ovulatory women were analyzed. All groups were similar in terms of demographically except for gravidity and parity [Table 1].

Table 1. Demographic and baseline data of the group

Data are presented as mean ± standard deviation, *; Kruskal Wallis test, BMI: Body Mass Index, Endo: Endometrioma; PCOS; Polycystic Ovary Syndrome, US: Unexplained Subfertility

There were statistically significant differences between fertile group and each ones of study groups as expected.

Table 2 shows the distribution of IGFBP – 1, PGE2 and OPN levels. All markers were statistically different within all groups.

Table 2. The distribution of IGFBP – 1, PGE2 and OPN

Data are presented as mean ± standard deviation, Endo; Endometrioma, IGFBP-1; insulin-like growth factor binding protein 1, PCOS; Polycystic Ovary Syndrome,  PGE2; prostoglandin E2, OPN; osteopontin, US; Unexplained Subfertility, *; Kruskal Wallis test, ; ovulatory PCOS vs control group

The comparison of IGFBP – 1, PGE2 and OPN levels between study groups and control group is given in Table 3.

          Table 3. The comparison of IGFBP-1, PGE2 and OPN levels between the two groups

Endo; Endometrioma, IGFBP-1; insulin-like growth factor binding protein 1, PGE2; prostoglandin E2, OPN; osteopontin, PCOS; Polycystic Ovary Syndrome, US: Unexplained Subfertility, *; Mann Whitney U test

 Within all markers, only PGE2 levels were higher in ovulatory PCOS group (367.75±96.37) compared to control group (239.25±106.97). The difference was statistically significant (0.002).   

Discussion

In this prospective cross-sectional study, our aim was to compare the levels of IGFBP-1, osteopontin and PGE2 in the endometrial washing fluids of healthy, fertile women and patients with ovulatory PCOS, endometrioma and unexplained subfertility during implantation window. PGE2 levels were significantly higher in the ovulatory PCOS patients than in the control group.

There is increasing evidence regarding the irregular expression of uterine receptivity markers in the endometrium of women with ovulatory PCOS. Navarra et al [17] determined significantly high PGE2 levels in polycystic ovaries. In another study, it was reported that in patients receiving in vitro fertilization and ovum donation, PGE2 levels in the endometrial fluid increased substantially during the implantation window [16]. They reported that 24 hours prior to embryo transfer, PGE2 levels might predict pregnancy results and thus, PGE2 might be the potential non-invasive biomarker of endometrial receptivity. These findings are similar to the results of our study. Elevated PGE2 in ovulatory PCOS accompanies reduced a tendency to apoptosis. This has been observed by Ryu et al [18] in the endometrial cells. It is known that cells over secreting COX-2 have inability to increase proliferation and the ability to escape from apoptosis. The Gap 1 phase of this cell cycle is prolonged [19]. In addition to the basics of physiopathology appearing to be the increased apoptosis inhibition in the endometrial cells, PGE2 may contribute to endometrial dysfunction with its effects on cell proliferation, angiogenesis and immunosuppression by affecting the estrogen levels.

Low IGFBP-1 was shown in PCOS and obesity, but there were some inconsistencies in the literature. In the study of Kelly et al [20], IGFBP-1 levels were detected significantly lower in the ovulatory PCOS group compared to the control group. In obese PCOS patients, IGFBP-1 was lower than the normal weight patients with ovulatory PCOS. No significant difference was observed between obese PCOS-obese control groups and normal-weight control groups with PCOS. Reduced IGFBP-1 in ovulatory PCOS was related to ovarian hyperandrogenism mechanism. BMI was determined by Kelly et al [20] as the main determinant of serum IGFBP-1. Considering that the BMI of ovulatory PCOS group was high (28.6 kg/m2), it may explain the low levels of IGFBP-1 in our study, even though it was not statistically significant. In a recent study; mid-luteal OPN levels indicated similar distributions in ovulatory PCOS phenotype patients compared to controls [21]. A significant reduction was observed in OPN levels in infertile women with isolated PCO. However, in this study ovulatory dysfunction was the main reason for subfertility. The contradictory results affect the comparability of this data compared to our study.

For the endometrioma group of our study, IGFBP-1, OPN and PGE2 levels in mud-luteal phase were similar to the control group. It is known that genetic factors are related to the development and progression of endometriosis; however, genes related to endometriosis are not identified. It is believed that IGFBPs play an important role in cell apoptosis, proliferation and pathophysiology of endometriosis. In one study, it was determined that IGFBP-1 was not associated with endometriosis whereas IGFBP-3 was significantly associated with endometriosis [22]. αvβ3 integrin and osteopontin, the extracellular matrix ligand thereof, play a role in the regulation of endometrial receptivity. While osteopontin expression was not affected in women with endometriosis, it was shown that αvβ3 integrin expression was reduced. Interestingly, when αvβ3 expression is lacking, OPN’s binding to the surface epithelium is quite limited. This evidence indicates that the endometrium of some women with endometriosis is dysfunctional and responsible for the decrease in fecundity [23]. In our study, relative elevation in OPN and IGFBP-1 levels may affect negatively both the inhibition of apoptosis as well as embryo implantation in the implantation window.

In our study, in the unexplained subfertility group, IGFBP-1, OPN and PGE2 levels in the midluteal phase were similar to the control group. Studies investigating unexplained subfertility and endometrial dysfunction in the implantation window are limited in literature. Recently, osteopontin and its receptor αvβ3 integrin were suggested as important complexes in embryo implantation and therefore they may be useful as endometrial receptivity markers. In one study, no statistically significant differences were found in terms of αvβ3 integrin or osteopontin expression. Even though both glycoprotein concentrations were high in the 8th post-ovulation day, a significant lack in co-expressions during the implantation window period was observed. In a popular study Casals et al [14] concluded that the complex of αvβ3 and OPN was functional in endometrial receptivity and implantation.

The strengths of our study were that the markers studied were diverse and the numbers of subjects were sufficient. However, the weaknesses of our study were that the diagnosis of endometrioma was made by imaging methods; the control group consisted of coincidental, relatively older fertile women, owing to consecutive recruitment. The limitations of our study were lack of the power analysis. Therefore; although midluteal PGE2 expression was higher in the endometrioma patients and unexplained subfertility groups compared to the control group, the difference was not statistically significant.

In conclusion; ovulatory PCOS, unexplained subfertility and endometriosis were related to the disrupted endometrium receptivity in the literature. PGE2 might be an indicator of a reduced endometrial receptivity that might be responsible for the low pregnancy rates in ovulatory PCOS patients according to results of our study. Because a single biomarker that each of many genes expresses is not sufficient in explaining the implantation bio mechanism and high numbers of biomarkers play a role in endometrial receptivity, there is a need for a more extensive studies comprising a high number of markers for the endometrium receptivity in different infertility issues.

Disclosure statement

No potential conflict of interest was reported by the authors.

References

Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.

img

Virginia E. Koenig

Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.

img

Delcio G Silva Junior

Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.

img

Ziemlé Clément Méda

Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.

img

Mina Sherif Soliman Georgy

We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.

img

Layla Shojaie

The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.

img

Sing-yung Wu

Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.

img

Orlando Villarreal

Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.

img

Katarzyna Byczkowska

Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.

img

Anthony Kodzo-Grey Venyo

Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.

img

Pedro Marques Gomes

Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.

img

Bernard Terkimbi Utoo

This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.

img

Prof Sherif W Mansour

Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.

img

Hao Jiang

As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.

img

Dr Shiming Tang

Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.

img

Raed Mualem

International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.

img

Andreas Filippaios

Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.

img

Dr Suramya Dhamija

Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.

img

Bruno Chauffert

I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!

img

Baheci Selen

"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".

img

Jesus Simal-Gandara

I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.

img

Douglas Miyazaki

We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.

img

Dr Griffith

I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.

img

Dr Tong Ming Liu

I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.

img

Husain Taha Radhi

I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.

img

S Munshi

Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.

img

Tania Munoz

“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.

img

George Varvatsoulias

Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

img

Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

img

Khurram Arshad